The formation of lymphomas in response to murine leukemia virus (MLV) infection is dependent on MLV persistence and avoidance of immune clearance. Immuno-competent adult mice are typically resistant to the development of lymphoma. In contrast, neonatal animals and immuno-suppressed adults are highly susceptible to MLV-dependent leukemogenesis. We recently determined that Gross murine leukemia virus )G-MLV) induced leukemia in adult when injected intra-thymically. We propose that thymic infection is an essential component of both the abrogation of virus immunity and prolonged exposure to immature thymocytes, the susceptible targets of transformation. Our studies utilize the well characterized molecular clone of G-MLV, GD-17. The thymo- tropism of GD-17 is controlled by unique sequences within the long- terminal leukemogenesis through the creation and in vivo expression of G-MLV based vectors. During the pre-leukemic phase, integrated virus and virus protein expression is detected predominantly in adult medullary thymic adult mice is uniformly linked to inhibition of anti-G-MLV immunity. The proposed studies address the hypothesis that replication of MLV in mTEC is an essential component of immune tolerance, persistent virus infection, and leukemogenesis. AIM 1: TO DETERMINE THE ROLE OF EPITHELIAL CELL TROPISM IN THE INHIBITION OF IMMUNE RESPONSES TO MLV AIM 2: TO DETERMINE THE MECHANISM OF TOLERANCE INDUCTION BY THYMO-TROPIC MLV AIM 3: TO DETERMINE THE REQUIREMENTS OF THYMIC G- MLV INFECTION ON IMMUNE TOLERANCE AND LEUKOMOGENESIS